This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic (05-HL-102) Treatment of Obstructive Sleep Apnea. About 15-30% of obstructive sleep apnea (OSA) patients have a poor tolerance for nasally-applied continuous positive airway pressure (CPAP) or develop problematic central apneas in response to this standard care. Although various alternative therapies have been tried, there is so far still no effective management for these refractory or difficult cases, probably because most available treatments are merely aimed at reducing the upper airway (UAW) collapsibility in unselected patients without concern for the dominant mechanism causing each individual's OSA. Recent research has revealed that breathing instability during sleep is more significant in those OSA patients who show high controller gain (ventilatory response to change of PaCO2) and/or high plant gain (eupnea PaCO2) of the respiratory control system, as manifested by a reduced CO2 reserve [?(eupneic PaCO2-apneic threshold PaCO2 )]. As we reported previously, periodic breathing and central apnea often lead to cyclical airway obstruction at the nadir of the respiratory drive in subjects with more collapsible upper airways. Accordingly, we hypothesize that correcting respiratory system instability will improve airway patency and breathing for those patients who are characterized by a significantly unstable respiratory motor output with mild to moderate levels of UAW collapsibility. This approach will be less effective with those who demonstrate less significant control instability and/or have extremely severe UAW collapsibility. We will characterize airway collapsibility and respiratory control system stability in 30 OSA patients. Then we will examine the effects on apnea/hypopnea index (AHI) and O2 desaturation of three different therapeutic strategies in these patients with a wide spectrum of breathing stability and UAW collapsibility:(1) prevention of transient hypocapnia via a unique iso-capnic rebreathing application;(2) reduction of plant gain via acetazolamide;and (3) a dampening of controller gain via hyperoxia, during sleep. We hypothesize that (1) Preventing transient hypocapnia should have the most significant effect of all three treatments on AHI in a broader range of OSA patients because it will prevent reductions in such a powerful determinant (i.e. PaCO2) of both upper airway and chest wall muscle recruitment as well as of respiratory system stability. Accordingly, we would expect this treatment to significantly reduce AHI even in patients with moderate airway collapsibility and with unstable ventilatory control. (2) Increasing respiratory motor output and reducing plant gain via carbonic anhydrase inhibition (and mild metabolic acidosis) will eliminate central apneas and significantly reduce obstructed and mixed apneas in subjects with a narrowed CO2 reserve due to increased plant or controller gain combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant degrees of underlying breathing instability. (3) Hyperoxia will improve breathing stability and reduce OSA by reducing loop gain in OSA patients with a narrowed CO2 reserve (mainly due to increased controller gain) combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant breathing instability. We anticipate that AHI in patients with even more severely unstable and collapsible UAW will not be improved by any of the three treatments because even a substantial amount of increased motor output to these dilator muscles during sleep will not be sufficient to open or prevent closure of such high collapsible airways. Arousal and wakefulness are likely required for airway patency in these patients. The proposed studies will deepen our understanding of the importance of heteropathy for each phenotype of OSA and will pave the way for individually targeted treatment approaches for managing refractory OSA. PUBLIC HEALTH RELEVANCE: We hope to improve the breathing during sleep in patients with OSA by individualizing their treatment to the patients'specific problem(s) associated with upper airway collapsibility and/or breathing stability.